Tae Hyun KimCenter for Liver Cancer, National Cancer Center

Low Radiation Dose effect of Tomotherapy for Hepatocellular Carcinoma

Surgery, local ablative treatments (i.e., radiofrequency ablation [RFA], percutaneous ethanol

injection [PEI]), transarterial chemoembolization (TACE), and liver transplantation are well

established treatment modalities for hepatocellular carcinoma (HCC)

In cases that these treatments are ineffective or unsuitable, radiotherapy (RT) with X-ray

could be safe and effective alternativeSeong J. Int J Radiat Oncol Biol Phys 2000;47:1331-1335

Kim TH et al. Am J Clin Oncol 2006;29:568-575

Tomotherapy - is capable of intensity modulation using helical beams as well as imaging guidance - Several previous studies for HCC patients with or without PVTT have showed promising results, i.e., better tumor response, better overall survival in responsive subgroup, and low rate of acute and late toxicities.

Kim JY et al. Radiat Oncol 2013;8:15

Hseih CH et al. Radiat Oncol 2010;5:40

Jang JW et al. Int J Radiat Oncol Biol Physics 2009;74:412-418

Tomotherapy for Hepatocellular Carcnioma

Plan Comparisons: IMRT vs. Tomotherapy

Coplannar IMRT Non-coplannar IMRT

Tomotherapy

Hseih CH et al. Radiat Oncol 2010;5:40

Conformality of Target coverageTomotherapy>Non-coplannar IMRT>Coplanner IMRT

Low dose of radiation to liverNon-coplannar IMRT>Coplanner IMRT>Tomotherapy

Low Radiation Dose Effect of Tomotherapy for Hepatocellular Carcinoma

A high dose of radiation can be delivered to the small volume of liver without influence in function.

In RT planning, irradiated volume of liver receiving low dose of radiation (≤ 10Gy) is less concerned than irradiated volume of liver receiving a high dose of radiation

Q. Is low dose of radiation (≤10Gy), to liver negligible? or Is low dose of radiation not related with RT induced hepatic toxicity?

Lawrence TS et al. Int J Radiat Oncol Biol Phys 1992;23:781-788

The portion of un-irradiated liver has a very strong potential ability of regeneration and functional compensation

Radiation Tolerance Dose of Liver: depend on irradiated liver volume

Irradiated liver volume

Tolerance dose

100% 30 - 35Gy

70% 42Gy

50% 52Gy

20% 70Gy

Radiation induced Hepatic Toxicity Classic radiation induced liver disease (RILD)

- Induced by veno-occlusive disease, severe congestion and fibrosis of the sinosoids in central portion of lobules with atrophy the inner portion of liver plates

- Clinical manifestations: anicteric ascites, elevated alkaline phosphatase (ALP), and minimal or no increase bilirubin Lawrence TS et al. Int J Radiat Oncol Biol Phys 1995;31:1237-1248

Non-classic radiation induced hepatic toxicity (RIHT), mostly in HBV endemic areas

- Induced by hepatocyte damage.

- Clinical manifestations: elevated aminotransferase (ALT) and elevated bilirubin.

Cheng JC et al. Int J Radiat Oncol Biol Phys 2002;54:156-625

Kim TH et al. Int J Radiat Oncol Biol Phys 2007;67:225-31

HBV reactivation and CHB exacerbation

- Increase of >1x log10 IU/mL.

- HBV reactivation,

and ≥2 times baseline level of ALT. Hoofnagel Hepatology 2009;49:s156-165

Q. Is non-classic RIHT related with HBV reactivation?

Hepatitis reactivation and RT

RT group

RT group

Not all non-classic RILD was related with HBV reactivation, but some proportion of non-classic RILD might be related with HBV reactivation.

Kim JH et al Int J Radait Oncol Biol Phys 2007;69:813-819

Q. Does radiotherapy induce the HBV reactivation?

Control group

Hepatitis reactivation and RT HBV reactivation

- can be spontaneous, but is most commonly triggered by cancer chemotherapy, immune suppression, or alteration of immune function.

- Can lead to clinically apparent acute hepatitis, such as elevation of ALT and bilirubin.

Q. What is cause of HBV reactivation by radiotherapy?

(4Gy)

Non-cytotoxic low dose of radiation to liver can induce releasing of the inflammatory cytokines, including IL-6, from endothelial cells and subsequently can induce HBV reactivation

Chou CH et al Clin Cancer Res 2007;13:851

Low Radiation Dose Effect of Tomotherapy for Hepatocellular Carcinoma

A: Low dose of radiation is safe, but not negligible.

Especially in HBV endemic area, low dose of radiation might have a potential to induce the HBV reactivation and/or CHB exacerbation and thus we should be minimize the low dose of radiation and monitor the HBV DNA level carefully after RT

Irradiated liver volume

Tolerance dose

100% 30 - 35Gy

70% 42Gy

50% 52Gy

20% 70GyLawrence TS et al. Int J Radiat Oncol Biol Phys 1992;23:781-788

Q. Is low dose of radiation (less than 10Gy) to liver safe or negligible? or Is low dose of radiation not related with RT induced hepatic toxicity?

Coplannar IMRT Non-coplannar IMRT

Tomotherapy

Hseih CH et al. Radiat Oncol 2010;5:40

Target coverageTomotherapy>Non-coplannar IMRT>Coplanner IMRT

Low dose of radiation to liverNon-coplannar IMRT>Coplanner IMRT>Tomotherapy

Low Radiation Dose Effect of Tomotherapy for Hepatocellular Carcinoma

Is a risk of HBV reactivation and/or CHB exacerbation higher in Tomotherapy than IMRT or other RT modalities?

There are no comparison study until now, and thus further clinical studies should be warranted.

Low Radiation Dose Effect of Tomotherapy for Hepatocellular Carcinoma

The most common and important obstacle to conducting the clinical trial regarding Tomotherapy for HCC patients and applying it in clinical practice.

- National Insurance do not cover the Tomotherapy for HCC patients, and thus patients’ burden for Tomotherapy is high.

- To apply Tomotherapy for HCC patients as a common clinical practice, the research support for clinical trial comparing Tomotherapy with other RT modalities should be needed